title: Loss of SHP-2 activity in CD4+ T cells promotes melanoma progression and metastasis.
abstract: The Src homology 2 domain-containing tyrosine phosphatase 2 (SHP-2) has been reported to have both tumor-promoting and tumor-suppressing roles in tumorigenesis. However, the role of SHP-2 in tumor immunity remains unclear. Here we observed progressively lower levels of phosphorylated SHP-2 in tumor-associated CD4(+) T cells during melanoma development in a murine model. Similarly, the levels of phosphorylated SHP-2 in the CD4(+) T cells of human melanoma specimens revealed a decrease paralleling cancer development. The CD4(+) T cell-specific deletion of SHP-2 promoted melanoma metastasis in mice. Furthermore, SHP-2 deficiency in CD4(+) T cells resulted in the increased release of inflammatory cytokines, especially IL-6, and the enhanced accumulation of tumor-promoting myeloid-derived suppressor cells (MDSCs) in tumor-bearing mice. An IL-6-neutralizing antibody reduced MDSC accumulation and inhibited tumor growth in CD4(+) T-cell-specific SHP-2-knockout mice. Our results suggest that SHP-2 in CD4(+) T cells plays an important role in preventing melanoma progression and metastasis.
authors.affiliation: 1] State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China [2].
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Wenjie
authors.initials: W
authors.lastname: Guo
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Lele
authors.initials: L
authors.lastname: Guo
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Gu
authors.forename: Yongqian
authors.initials: Y
authors.lastname: Shu
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.forename: Zichun
authors.initials: Z
authors.lastname: Hua
authors.forename: Yuehai
authors.initials: Y
authors.lastname: Ke
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology / Q000556:secondary*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000556:secondary*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11